PROJECT SUMMARY Due to increasing average life expectancy, along with the high incidence of cardiovascular disease in aging, more than half of all cardiovascular procedures are performed in adults over 65 years of age. However, despite overall favorable safety profiles, older adults have an increased susceptibility to adverse outcomes. Indeed, exposure to cardiovascular procedures intended to promote survival may instead precipitate long-term disease and disability. A better understanding of resilience and vulnerability (i.e. why some individuals successfully navigate health stressors while others do not) may help identify physiologic factors that affect recovery potential and long-term wellbeing. The goal of this work is to take the first steps in identifying a potentially modifiable molecular indicator of vulnerability in patients with cardiovascular disease. Transcatheter aortic valve replacement (TAVR) is a minimally invasive alternative to surgical aortic valve replacement for those with symptomatic severe aortic stenosis (AS). Although over 70% of TAVR patients achieve improved quality of life (QoL) and prolonged survival, poor outcomes such as mortality and functional decline remain common. Clinical factors like the burden of cardiovascular disease, comorbidities, and frailty predict worse outcomes. Furthermore, preliminary data suggests that increased markers of inflammation and dysregulated immune activity are associated with worse outcomes, as well. A better understanding of the relationship between inflammatory and immune activity and outcomes after TAVR may point to mechanisms mediating vulnerability and suggest targets for intervention. Relevant to this, although never before explored in relation to cardiovascular procedures, a specific gene expression pattern known as the conserved transcriptional response to adversity (CTRA) is associated with adverse outcomes after exposure to a health stressor. Defined by the simultaneous upregulation of inflammation and downregulation of innate immune responses, CTRA expression prior to health-stress exposure predicts adverse events such as poor QoL and mortality. Importantly, CTRA expression is modifiable, and pharmacologic and behavioral interventions that successfully downregulate CTRA are associated with improved clinical outcomes. Therefore, this project explores the hypothesis that increased CTRA expression at baseline, as a marker of inflammatory and immune system dysfunction, will predict adverse long-term outcomes after TAVR. By identifying gene expression patterns that relate to increased vulnerability, the results will provide a foundation for future work exploring physiologic mechanisms that contribute to diminished resilience, and highlight potential targets for therapeutic manipulation to optimize outcomes. Furthermore, this project will support my professional development through mentored acquisition of research and leadership skills necessary to become a successful independent researcher with a transdisciplinary approach to understanding healthful aging in older adults with cardiovascular disease.